Nonsteroidal antuinflammatory drugs (NSAID's) have been the mainstay of antirheumatic and antunflammatory drug therapy for over 200 years (Weissman, G., Scientific American 84-90, 1991). NSAID's function through inhibition of prostaglandin biosynthesis (Vane, J. R., Nature-New Biology 231, 232-235, 1971). Specifically, these agents act as cyclooxygenase (prostaglandin G/H synthase) inhibitors. Cyclooxygenase is the first enzyme in the arachidonic acid cascade, leading to prostaglandins of the D.sub.2, E.sub.2, and F.sub.2a series. In addition, prostacyclin (PGI.sub.2) and thromboxanes A.sub.2 and B.sub.2 are derived from a cyclooxygenase-generated PGHS.sub.2 intermediate (Prostaglandins and Related Substances--A Practical Approach (1987). Benedetto, C., McDonald-Gibson, R. G., and Nigam, S., and Slater, T. F., eds. IRL Press, Washington, D.C). These arachidonic acid metabolites are involved in the processes of pain, fever, blood clotting and inflammation. In addition, prostaglandins are responsible for maintaining gastrointestinal mucosal integrity (Cryer, B., and Feldman, M., Arch Intern. Med. 152, 1145-1155, 1992) and renal function, particularly under conditions of stress (Whelton, A., and Hamilton, C. W., J. Clin. Pharmacol. 31, 588-598, 1994). Thus, agents which inhibit the cyclooxygenase enzyme have beneficial antiinflammatory and analgesic properties due to blockade of inflammatory and pain-mediator production, but by virtue of their mechanism of action, these same agents have liabilities associated with gastrointestinal and renal function. Minimizing or eliminating these-liabilities in a new therapy provides the rationale for searching for a "safe" NSAID with an improved GI and renal profile (Vane, J. R., Nature 367, 215-216, 1994).
Until recently, it had been assumed that only one cyclooxygenase isozyme was responsible for all prostaglandin G/H2 synthase activity. However, a newly identified, mitogen-inducible form of this enzyme, termed cyclooxygenase 2 (Cox 2), has been described (Xie, W., Chipman, J. G., Robertson, D. L., Erickson, R. L., and Simmons, D. L., Proc. Natl. Acad. Sci. 88, 2692-2696, 1991; Kujubu, D. A., Fletcher, B. S., Varnum, B. C., Lim, R. W., and Herschman, H. R., J. Biol Chem. 266(20) 12866-12872, 1991; Hla, T., and Neilson, K., Proc. Natl. Acad. Sci. 89, 7384-7388, 1991; Xie, W., Robertson, D. L., and Simmons, D. L., Drug Development Research 25, 249-265, 1992). Cox 2 displays physical and biological properties distinct from the classic cyclooxygenase species, Cox 1. The tissue and cellular distribution of Cox 2, along with its regulated expression, implicate its involvement in inflammatory responses and disease states such as rheumatoid arthritis, while Cox 1 expression is responsible for constitutive functions. Based upon the distinction between Cox 1 and Cox 2, the previous hypotheses explaining NSAID effects, which rely on a single isozyme, must be questioned. Specifically, the antiinflammatory and analgesic action of NSAID's attributed exclusively to inhibition of the constitutive Cox 1 isozyme cannot be accepted. In fact, a more probable hypothesis is that the antiinflammatory and analgesic action of most NSAID's in response to a chronic stimulus can be accounted for by inhibition of the inducible Cox 2 species, while GI and renal liabilities of existing NSAID's are due to inhibition of the constitutively expressed Cox 1 enzyme (Vane, J. R., Nature 367, 215-216, 1994). Thus, agents which possess selective or specific inhibition of Cox 2 can be expected to provide improved GI and renal safety while maintaining a high degree of antiinflammatory, antipyretic and analgesic activity.
The potential for a safer NSAID through selective inhibition has prompted evaluation of compounds on purified enzyme preparations. Preferential inhibition of either isoenzyme or equal inhibitory potency has been obtained with a collection of therapeutically useful NSAIDS (DeWitt, D. L., Meade, E. A., and Smith, W. L., Amer. J. Med. 95 (Suppl. 2A), 40S-44S, 1993). Only one compound in this collection, however, displayed Cox 2 selectivity, namely 6-methoxy naphthylacetic acid (6MNA), the nebumetone active metabolite. Several other agents with similar Cox-2 selectivity have also been described including BF389 (Mitchell, J. A., Akarasereenot, P., Thiemermann, C., Flower, R. J., and Vane, J. R., Proc. Natl. Acad. Sci. 90, 11693-11697, 1994) and NS-398 (Futaki, N., Takahashi, S., Yokayama, M., Arai, I., Higuchi, S., and Otomo, S., Prostaglandins 47, 55-59, 1994; Masferrer, J. L., Zuieifel, B. S., Manning, P. T., Hauser, S. D., Leaky, K. M., Smith, W. G., Isakson, P. C., and Seibert, K., Proc. Natl. Acad. Sci. 91, 3228-3232, 1994). With the latter compound, selective inhibition of Cox-2 blocked proinflammatory prostaglandin synthesis in vivo in response to carrageenan, but did not block gastric prostaglandin synthesis nor produce gastic lesions (Masferrer et al, vide supra).
The findings support the premise that selective Cox-2 inhibitors will possess potent antiiflammatory properties and improved safety profile. Detailed mechanistic studies have revealed that NS-398 along with a second Cox-2 selective inhibitor, DuP 697, achieve their selectivity through a unique process (Copeland, R. A., Williams, J. M., Giannaras, J., Nurnberg, S., Covington, M., Pinto, D., Pick, S., and Trzaskos, J. M. Mechanism of Selective Inhibition of the Inducible Isoform of Prostaglandin G/H Synthase. Submitted). The inhibition is competitive toward both isoenzymes, but displays selective time-dependence against Cox-2 resulting in enhanced inhibition with longer exposure. Time-dependence produces an extremely tight binding inhibition which can only be reversed following enzyme denaturation and organic extraction.
Newkome G. R. et. al. (J. Org. Chem. 1980, 45, 4380) report bis-(5-carboxy-2-pyridyl)benzenes, but no utility for these compounds is disclosed. ##STR2##
Bushby et. al. (J. Chem. Soc. Perkin Trans. I 721, 1986) describe the synthesis of substituted terphenyls including the example shown below. ##STR3##
Hori M. et. al. ( Chem. Pharm. Bull. 22(9), 2020, 1974,) report the synthesis of terphenyls, including 2-phenyl-2'-methylthio-1-biphenyl. ##STR4##
Kemp et. al. (J. Org. Chem. 46, 5441, 1981), report the synthesis of 4-methoxyphenyl-(4'-alkylphenyl) benzenes. ##STR5##
Floyd et. al., U.S. Pat. No. 4,613,611 disclose a-hydroxy-b-oxo-1,1':2',1"-terphenyl!-4-ethanesulfonic acid, monosodium salt for the treatment of Diabetes Mellitus. ##STR6##
Ortho-bis(dimethoxyphenyl)benzene carboxamides have been reported (Tilley, et. al. J. Med. Chem. 32, 1814, 1989) as platelet-activating factor antagonists. ##STR7##
European Patent Application EP130045 A1, published Jan. 2, 1985 discloses substituted bis-(methoxyphenyl)benzenes as analgesic and antiinflammatory agents. ##STR8##
U.S. Pat. No. 3,624,142 discloses 4-methylsulfonyl-biphenylacetic acids as antiflammatory agents. ##STR9##
None of the above references teach or suggest the methylsulfonyl compounds of the present invention. Thus, it is the object of the present invention to provide compounds which are prostaglandin synthase inhibitors, including compounds which are selective Cox 2 inhibitors, as novel antiinflammatory agents with an improved therapeutic profile for use in rheumatic and inflammatory diseases and in the treatment of pyresis.